Citric acid cycle

Overview of the citric acid cycle (click to enlarge)

The citric acid cycle — also known as the tricarboxylic acid cycle (TCA cycle), or the Krebs cycle.^[1][2] — is a series of chemical reactions used by all aerobic organisms to generate energy through the oxidization of acetate derived from carbohydrates, fats and proteins into carbon dioxide. In addition, the cycle provides precursors including certain amino acids as well as the reducing agent NADH that is used in numerous biochemical reactions. Its central importance to many biochemical pathways suggests that it was one of the earliest established components of cellular metabolism and may have originated abiogenically.^[3]

The name of this metabolic pathway is derived from citric acid (a type of tricarboxylic acid) that is first consumed and then regenerated by this sequence of reactions to complete the cycle. In addition, the cycle consumes acetate (in the form of acetyl-CoA) and water, reduces NAD⁺ to NADH, and produces carbon dioxide. The NADH generated by the TCA cycle is fed into the oxidative phosphorylation pathway. The net result of these two closely linked pathways is the oxidation of nutrients to produce usable energy in the form of ATP.

In eukaryotic cells, the citric acid cycle occurs in the matrix of the mitochondrion. Bacteria also use the TCA cycle to generate energy, but since they lack mitochondria, the reaction sequence is performed in the cytosol with the proton gradient for ATP production being across the plasma membrane rather than the inner membrane of the mitochondrion.

Several of the components and reactions of the citric acid cycle were established in the 1930s by the research of the Nobel laureate Albert Szent-Györgyi, for which he received the Nobel Prize in 1937 for his discoveries pertaining to fumaric acid, a key component of the cycle.^[4]

The citric acid cycle itself was finally identified in 1937 by Hans Adolf Krebs whilst at the University of Sheffield, for which he received the Nobel Prize for Physiology or Medicine in 1953.^[5]

Evolution [edit]

Components of the TCA cycle were derived from anaerobic bacteria, and the TCA cycle itself may have evolved more than once.^[6] Theoretically there are several alternatives to the TCA cycle, however the TCA cycle appears to be the most efficient. If several TCA alternatives had independently evolved, they all appear to have converged onto the canonical TCA cycle.^[7][8]

Overview [edit]

The citric acid cycle is a key component of the metabolic pathway by which all aerobic organisms generate energy. Through catabolism of sugars, fats, and proteins, a two carbon organic product acetate in the form of acetyl-CoA is produced. Acetyl-CoA along with two equivalents of water (H₂O) is consumed by the citric acid cycle producing two equivalents of carbon dioxide (CO₂) and one equivalent of HS-CoA. In addition, one complete turn of the cycle converts three equivalents of nicotinamide adenine dinucleotide (NAD⁺) into three equivalents of reduced NAD⁺ (NADH), one equivalent of ubiquinone (Q) into one equivalent of reduced ubiquinone (QH₂), and one equivalent each of guanosine diphosphate (GDP) and inorganic phosphate (P_i) into one equivalent of guanosine triphosphate (GTP). The NADH and QH₂ generated by the citric acid cycle are in turn used by the oxidative phosphorylation pathway to generate energy-rich adenosine triphosphate (ATP).

One of the primary sources of acetyl-CoA is sugars that are broken down by glycolysis to produce pyruvate that in turn is decarboxylated by the enzyme pyruvate dehydrogenase generating acetyl-CoA according to the following reaction scheme:

• CH₃C(=O)C(=O)O^– (pyruvate) + HSCoA + NAD⁺ → CH₃C(=O)SCoA (acetyl-CoA) + NADH + CO₂

The product of this reaction, acetyl-CoA, is the starting point for the citric acid cycle. Below is a schematic outline of the cycle:

• The citric acid cycle begins with the transfer of a two-carbon acetyl group from acetyl-CoA to the four-carbon acceptor compound (oxaloacetate) to form a six-carbon compound (citrate).
• The citrate then goes through a series of chemical transformations, losing two carboxyl groups as CO₂. The carbons lost as CO₂ originate from what was oxaloacetate, not directly from acetyl-CoA. The carbons donated by acetyl-CoA become part of the oxaloacetate carbon backbone after the first turn of the citric acid cycle. Loss of the acetyl-CoA-donated carbons as CO₂ requires several turns of the citric acid cycle. However, because of the role of the citric acid cycle in anabolism, they may not be lost, since many TCA cycle intermediates are also used as precursors for the biosynthesis of other molecules.^[9]
• Most of the energy made available by the oxidative steps of the cycle is transferred as energy-rich electrons to NAD⁺, forming NADH. For each acetyl group that enters the citric acid cycle, three molecules of NADH are produced.
• Electrons are also transferred to the electron acceptor Q, forming QH₂.
• At the end of each cycle, the four-carbon oxaloacetate has been regenerated, and the cycle continues.

Steps [edit]

Two carbon atoms are oxidized to CO₂, the energy from these reactions being transferred to other metabolic processes by GTP (or ATP), and as electrons in NADH and QH₂. The NADH generated in the TCA cycle may later donate its electrons in oxidative phosphorylation to drive ATP synthesis; FADH₂ is covalently attached to succinate dehydrogenase, an enzyme functioning both in the TCA cycle and the mitochondrial electron transport chain in oxidative phosphorylation. FADH₂, therefore, facilitates transfer of electrons to coenzyme Q, which is the final electron acceptor of the reaction catalyzed by the Succinate:ubiquinone oxidoreductase complex, also acting as an intermediate in the electron transport chain.^[10]

The citric acid cycle is continuously supplied with new carbon in the form of acetyl-CoA, entering at step 1 below.^[11]

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TCA Cycle edit

See also [edit]

• Calvin cycle
• Glyoxylate cycle
• Reverse (Reductive) Krebs cycle

References [edit]

External links [edit]

• An animation of the citric acid cycle at Smith College
• Citric acid cycle variants at MetaCyc
• Pathways connected to the citric acid cycle at Kyoto Encyclopedia of Genes and Genomes
• Introduction at Khan Academy

v t e Citric Acid Cycle Metabolic Pathway
			Oxaloacetate			Malate			Fumarate			Succinate			Succinyl-CoA
Acetyl-CoA				NADH + H+	NAD+			H2O		FADH2	FAD		CoA + ATP(GTP)	Pi + ADP(GDP)
	+	H2O														NADH + H+ + CO2
		CoA														NAD+
					H2O		H2O			NAD(P)+	NAD(P)H + H+			CO2
			Citrate			cis-Aconitate			Isocitrate			Oxalosuccinate			α-Ketoglutarate
M: MET mt, k, c/g/r/p/y/i, f/h/s/l/o/e, a/u, n, m k, cgrp/y/i, f/h/s/l/o/e, au, n, m, epon m (A16/C10), i (k, c/g/r/p/y/i, f/h/s/o/e, a/u, n, m)

v t e Metabolism map Glucuronate metabolism Pentose interconversion Inositol metabolism Cellulose and sucrose metabolism Starch and glycogen metabolism Other sugar metabolism Pentose phosphate pathway Glycolysis and Gluconeogenesis Amino sugars metabolism Small amino acid synthesis Branched amino acid synthesis Purine biosynthesis Histidine metabolism Aromatic amino acid synthesis Pyruvate decarboxylation Fermentation Fatty acid metabolism Urea cycle Aspartate amino acid group synthesis Porphyrins and corrinoids metabolism Citric acid cycle Glutamate amino acid group synthesis Pyrimidine biosynthesis v t e All pathway labels on this image are links, simply click to access the article. A high resolution labeled version of this image is available here.